# PET Imaging of neurochemical transmission in cocaine use disorders

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $626,132

## Abstract

Cocaine use disorder (CUD) is a chronic disorder associated with numerous relapses and periods of
abstinence. Studies in CUD suggest that ~ 60 to 75% of abstinent addicts relapse over twelve months
(Aharonovich et al., 2003; Simpson et al., 1999). Documenting specific neurochemical abnormalities that
lead to relapse in individuals with CUD has the potential to accelerate the development of medications to
prevent relapse. Basic investigations postulate an imbalance between brain stress and anti-stress/resilience
systems as the underlying mechanism that drives negative reinforcement, craving, and relapse in addiction
(Koob, 2008). Nociceptin (N/OFQ), which binds to the nociceptive opioid peptide receptors (NOP) is a
critical component of the brain’s anti-stress system. N/OFQ exerts its anti-stress effect by counteracting the
functional effects of the primary stress-promoting neuropeptide corticotrophin releasing factor (CRF) in the
brain (Ciccocioppo et al., 2001). Studies have also shown that acute increases in CRF and stress are
countered by increased NOP receptor expression (~ 10% ) in brain regions that regulate stress such as the
bed nucleus of the stria terminalis (Rodi et al., 2008). PET studies with the NOP radiotracer [11C]NOP-1A
show increased binding to NOP in CUD compared to healthy controls (HC) (Narendran et al., 2019). PET
studies also show NOP receptors to upregulate (~ 15%) in response to an acute intravenous
hydrocortisone challenge (1 mg/Kg). NOP upregulation may represent an adaptive mechanism in the brain
to counteract stress-induced increases in cortisol and CRF. Here, we postulate a failure in this adaptive
mechanism as a reason that leads to relapse in CUD. CUD subjects and HC will be studied with [11C]NOP-
1A before and after an intravenous hydrocortisone challenge (aim 1). Hydrocortisone is used as a challenge
because it increases cortisol and CRF in brain regions that regulate stress. We hypothesize that
hydrocortisone-induced increases in [11C]NOP-1A binding (DVT) will be smaller in CUD relative to HC, and
this will be associated with less time to relapse in a 12-week follow up. Mechanistic studies have also
shown N/OFQ to act on ventral tegmental area/midbrain NOP receptors to inhibit the firing of dopamine
neurons and limit reward to cocaine (Murphy and Maidment, 1999; Parker et al., 2019). Imaging
amphetamine-induced dopamine release in a subset of CUD subjects who participate in aim 1 will allow us
to link midbrain NOP receptor expression with ventral striatum (VST) dopamine release and examine its role
in reinforcement (aim 2). The aims proposed in this study have the potential to clarify the role of N/OFQ and
NOP in stress, reward, and relapse in CUD.

## Key facts

- **NIH application ID:** 10459233
- **Project number:** 5R01DA026472-11
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** RAJESH NARENDRAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $626,132
- **Award type:** 5
- **Project period:** 2009-09-30 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10459233

## Citation

> US National Institutes of Health, RePORTER application 10459233, PET Imaging of neurochemical transmission in cocaine use disorders (5R01DA026472-11). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10459233. Licensed CC0.

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